This invention relates to certain pyrazole derivatives that inhibit p38 MAP kinase, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.
TNF and IL-1 have been shown to be central players in the pathological processes underlying many chronic inflammatory and autoimmune diseases. IL-1 is implicated in mediating or exacerbating diseases such as rheumatoid arthritis ((see., Arend, W. P. Arthritis and Rheumatism 38(2): 151-160, (1995)), osteoarthritis, bone resorption, toxic shock syndrome, tuberculosis, atherosclerosis, diabetes, Hodgkin""s disease (see., Benharroch, D.; et. al. Euro. Cytokine Network 7(1): 51-57) and Alzheimer""s disease. Excessive or unregulated TNF production has been implicated in mediating or exacerbating diseases such as rheumatoid arthritis ((see., Maini, R. N.; et. al. APMIS. 105(4): 257-263, (1997); Feldmann, M., J. of the Royal College of Physicians of London 30(6): 560-570, (1996); Lorenz, H. M.; et. al. J. of Immunology 156(4): 1646-1653, (1996)) osteoarthritis, spondylitis, sepsis, septic shock ((see., Abraham, E.; et. al. JAMA. 277(19):1531-1538, (1997), adult respiratory distress syndrome, asthma ((see., Shah, A.; et. al. Clin. and Exp. Allergy 1038-1044, (1995) and Lassalle, P., et. al. Clin. and Exp. Immunol. 94(1): 105-110, (1993)), bone resorption diseases, fever ((see., Cooper, A. L., et. al. Am. J. of Physiology 267(6 Pt. 2): 1431-1436)), encephalomyelitis, demyelination ((see., Klindert, W. E.; et al. J. of Neuroimmunol. 72(2): 163-168, (1997)) and periodontal diseases.
Clinical trials with IL-1 and TNF receptor antagonists have shown that blocking the ability of these cytokines to signal through their receptors leads to significant improvement, in humans, in inflammatory diseases. Therefore, modulation of these inflammatory cytokines is considered one of the most effective strategies to block chronic inflammation and have positive therapeutic outcomes. It has also been shown that p38 MAP kinase plays an important role in the translational control of TNF and IL-1 and is also involved in the biochemical signaling of these molecules ((see., Lee, J. C., et al. Nature. 372 (6508): 73946, (1994)). Compounds that bind to p38 MAP are effective in inhibiting bone resorption, inflammation, and other immune and inflammation-based pathologies. The characterization of the p38 MAP kinase and its central role in the biosynthesis of TNF and IL-1 have made this kinase an attractive target for the treatment of diseases mediated by these cytokines.
It would therefore be desirable to provide p38 MAP kinase inhibitors and thereby provide a means of combating diseases mediated by pro-inflammatory cytokines such as TNF and IL-1. This invention fulfills this and related needs.
In a first aspect, this invention provides compounds selected from the group of compounds represented by Formula (I): 
wherein:
R1 is hydrogen or acyl;
R2 is hydrogen or alkyl;
A is an aryl or heteroaryl ring;
B is an aryl or heteroaryl ring;
R3 is selected from the group consisting of:
(a) amino, alkylamino or dialkylamino:
(b) acylamino;
(c) optionally substituted heterocyclyl;
(d) optionally substituted aryl or heteroaryl;
(e) heteroalkyl;
(f) heteroalkenyl;
(g) heteroalkynyl;
(h) heteroalkoxy;
(i) heteroalkylamino;
(j) optionally substituted heterocyclylalkyl;
(k) optionally substituted heterocyclylalkenyl;
(l) optionally substituted heterocyclylalkynyl;
(m) optionally substituted heterocyclylalkoxy, cyclyloxy or heterocyclyloxy;
(n) optionally substituted heterocyclylalkylamino;
(o) optionally substituted heterocyclylalkylcarbonyl;
(p) heteroalkylcarbonyl;
(q) xe2x80x94NHSO2R6 where R6 is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl;
(r) xe2x80x94NHSO2NR7R8 where R7 and R8 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(s) xe2x80x94Yxe2x80x94(alkylene)xe2x80x94R9 where:
Y is a single bond, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94S(O)nxe2x80x94 (where n is an integer from 0 to 2); and
R9 is cyano, optionally substituted heteroaryl, xe2x80x94COOH, xe2x80x94COR10, xe2x80x94COOR11, xe2x80x94CONR12R13, xe2x80x94SO2R14, xe2x80x94SO2NR15R16, xe2x80x94NHSO2R17 or xe2x80x94NHSO2NR18R19, where R10 is alkyl or optionally substituted heterocycle, R11 is alkyl, and R12, R13, R14, R15, R16, R17, R18 and R19 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(t) xe2x80x94C(xe2x95x90NR20)(NR21R22) where R20, R21 and R22 independently represent hydrogen, alkyl or hydroxy, or R20 and R21 together are xe2x80x94(CH2)nxe2x80x94 where n is 2 or 3 and R22 is hydrogen or alkyl;
(u) xe2x80x94NHC(X)NR23R24 where X is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, and R23 and R24 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(v) xe2x80x94CONR25R26 where R25 and R26 independently represent hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R25 and R26 together with the nitrogen to which they are attached form an optionally substituted heterocyclyl ring;
(w) xe2x80x94S(O)nR27 where n is an integer from 0 to 2, and R27 is alkyl, heteroalkyl, optionally substituted heterocyclylalkyl or xe2x80x94NR28R29 where R28 and R29 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(x) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino;
(y) arylaminoalkylene or heteroarylaminoalkylene;
(z) Z-alkylene-NR30R31 or Z-alkylene-OR32 where Z is xe2x80x94NHxe2x80x94, xe2x80x94N(alkyl)xe2x80x94 or xe2x80x94Oxe2x80x94, and R30, R31 and R32 are independently of each other, hydrogen, alkyl or heteroalkyl;
(aa) xe2x80x94OC(O)-alkylene-CO2H or xe2x80x94OC(O)xe2x80x94NRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl); and
(bb) heteroarylalkenylene or heteroarylalkynylene;
R4 is selected from the group consisting of.
(a) hydrogen;
(b) halo;
(c) alkyl;
(d) alkoxy; and
(e) hydroxy;
R5 is selected from the group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl;
(d) haloalkyl;
(e) thioalkyl;
(f) hydroxy;
(g) amino;
(h) alkylamino;
(i) dialkylarnino;
(j) heteroalkyl;
(k) optionally substituted heterocycle;
(l) optionally substituted heterocycylalkyl;
(m) optionally substituted heterocyclylalkoxy;
(n) alkylsulfonyl;
(o) aminosulfonyl, mono-alkylaminosulfonyl or dialkylaminosulfonyl;
(p) heteroalkoxy; and
(q) carboxy;
R6 is selected from a group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl; and
(d) alkoxy;
prodrugs, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.
In a second aspect, this invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
In a third aspect, this invention provides a method of treatment of a disease in a mammal treatable by administration of a p38 MAP kinase inhibitor, comprising administration of a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt.
In a fourth aspect, this invention provides processes for preparing compounds of Formula (I).
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
xe2x80x9cAlkylxe2x80x9d means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, pentyl, and the like.
xe2x80x9cAlkylenexe2x80x9d means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
xe2x80x9cAlkenylxe2x80x9d means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.
xe2x80x9cAlkenylenexe2x80x9d means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenylene, propenylene, and the like.
xe2x80x9cAlkynylxe2x80x9d means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like.
xe2x80x9cAlkynylenexe2x80x9d means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynylene, propynylene, and the like.
xe2x80x9cAlkoxyxe2x80x9d means a radical xe2x80x94OR where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, 2-propoxy, the like.
xe2x80x9cAcylxe2x80x9d means a radical xe2x80x94C(O)R where R is alkyl or haloalkyl e.g., acetyl, trifluoroacetyl, and the like.
xe2x80x9cAcylaminoxe2x80x9d means a radical xe2x80x94NRC(O)Rxe2x80x2 where R is hydrogen or alkyl, and Rxe2x80x2 is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, e.g., acetylamino, 2-amino-2-methylpropionamide, and the like.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo, or iodo, preferably fluoro and chloro.
xe2x80x9cHaloalkylxe2x80x9d means alkyl substituted with one or more same or different halo atoms, e.g., xe2x80x94CH2Cl, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CH2CCl3, and the like.
xe2x80x9cArylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl, 1-naphthyl, 2-naphthyl, and the like. The aryl ring may optionally be fused to a 5-, 6- or 7- membered monocyclic saturated ring optionally containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulfur, the remaining ring atoms being C where one or two C atoms are optionally replaced by a carbonyl group. Representative aryl radicals with fused rings include, but are not limited to, 2,3-dihydrobenzo[1,4]dioxan, chroman, isochroman, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran, benzo[1,3]dioxole, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-indole, 2,3-dihydro-1H-isoindole, benzimidazol-2-one, 3H-benzoxazol-2-one, and the like.
xe2x80x9cHeteroarylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. The term also includes those radicals where a heteroatom within the ring has been oxidized or quatemized, such as, for example, to form an N-oxide or a quaternary salt. Representative examples include, but are not limited to, thienyl, benzothienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, quinoxalinyl, imidazolyl, furanyl, benzofuranyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, 2-pyridonyl, 4-pyridonyl, N-alkyl-2-pyridonyl, pyrazinonyl, pyridazinonyl, pyrimidinonyl, oxazolonyl, and their corresponding N-oxides, (e.g. pyridyl N-oxide, quinolinyl N-oxide), their quaternary salts and the like.
xe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cheterocyclylxe2x80x9d means a cyclic nonaromatic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C where one or two C atoms are optionally replaced by a carbonyl group. The term also includes those radicals where a ring nitrogen atom has been oxidized or quaternized, such as, for example, to form an N-oxide or a quaternary salt. Representative examples include, but are not limited to, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidino, morpholino, piperazino, pyrrolidino, oxiranyl, dioxane, 1,3-dioxolanyl, 2,2-dimethyl-1,3-dioxalanyl, sulfolanyl, 2-oxazolidonyl, 2-imidazolidonyl, S,S-dioxo-thiomorpholino, and the like.
xe2x80x9cHeterocycloamninoxe2x80x9d means a saturated monovalent cyclic group of 4 to 8 ring atoms, wherein at least one ring atom is N and optionally contains one additional ring atom selected from N or O, the remaining ring atoms being C. The term includes groups such as pyrrolidino, piperidino, morpholino, piperazino and the like.
xe2x80x9cOptionally substituted aryl, heteroaryl or heterocyclylxe2x80x9d means an aryl, heteroaryl or heterocyclyl ring as defined above, which is optionally substituted independently with one or two substituents selected from alkyl, phenyl, benzyl, haloalkyl, heteroalkyl, halo, cyano, acyl, xe2x80x94OR (where R is hydrogen or alkyl), xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently selected from hydrogen, alkyl or acyl), xe2x80x94NHCOR (where R is alkyl), xe2x80x94NRS(O)nRxe2x80x2 (where R is hydrogen or alkyl, n is an nteger from 0 to 2 and Rxe2x80x2 is hydrogen, alkyl or heteroalkyl), xe2x80x94NRS(O)nNRxe2x80x2Rxe2x80x3 (where R is hydrogen or alkyl, n is an integer from 0 to 2 and Rxe2x80x2 and Rxe2x80x3 are independently hydrogen, alkyl or heteroalkyl), xe2x80x94S(O)nR (where n is an integer from 0 to 2 and R is hydrogen, alkyl or heteroalkyl), xe2x80x94S(O)nNRRxe2x80x2 (where n is an integer from 0 to 2 and R and Rxe2x80x2 are independently hydrogen, alkyl or heteroalkyl), xe2x80x94COOR, xe2x80x94(alkylene)COOR (where R is hydrogen or alkyl), xe2x80x94CONRxe2x80x2Rxe2x80x3 or xe2x80x94(alkylene)CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl).
xe2x80x9cHeteroalkylxe2x80x9d means an alkyl radical as defined above, carrying one, two or three substituents selected from xe2x80x94NRaRb, xe2x80x94ORc wherein Ra, Rb and Rc are independently of each other hydrogen, alkyl or acyl, or Ra and Rb together form heterocycloamino group. Representative examples include, but are not limited to, hydroxymethyl, acetoxymethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl, 2-acetylaminoethyl, 3-[pyrrolidin-1-yl]ethyl and the like.
xe2x80x9cHeteroalkenylxe2x80x9d means an alkenyl radical as defined above, carrying one or two substituents selected from xe2x80x94NRaRb, xe2x80x94ORc or xe2x80x94S(O)nRd wherein Ra, Rb and Rc are independently of each other hydrogen or alkyl, and Rd is alkyl or xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently of each other hydrogen or alkyl. Representative examples include, but are not limited to, 3-hydroxy-1-propenyl, 3-aminoprop-1-enyl, 2-aminosulfonylethenyl, 2-methylsulfonylethenyl, and the like.
xe2x80x9cHeteroalkynylxe2x80x9d means an alkynyl radical as defined above, carrying one or two substituents selected xe2x80x94NRaRb, xe2x80x94ORc, xe2x80x94S(O)nRd or xe2x80x94S(O)nNRRxe2x80x2 (where R and Rxe2x80x2 are independently of each other hydrogen or alkyl) wherein Ra, Rb and Rc are independently of each other hydrogen or alkyl, and Rd is alkyl and n is an integer from zero to two. Representative examples include, but are not limited to, 3-hydroxy-1-propynyl, 3-dimethylaminoprop-1-ynyl and the like.
xe2x80x9cHeteroalkoxyxe2x80x9d means a radical xe2x80x94OR where R is heteroalkyl group as defined above, e.g., 2-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypropoxy, 2-(1,3-dihydroxy)propoxy, 2-aminoethoxy, and the like.
xe2x80x9cHeteroalkylaminoxe2x80x9d means a radical xe2x80x94NRaRb where Ra is hydrogen or alkyl, and Rb is a heteroalkyl group as defined above, e.g., 2-hydroxyethylamino, 3-dimethylaminopropylamino, and the like.
xe2x80x9cOptionally substituted heterocyclylalkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group, and Rb is an optionally substituted heterocyclyl group as defined above e.g., 2-(morpholin-4-yl)ethyl, 3-(piperidin-1-yl)-2-methylpropyl, and the like.
xe2x80x9cOptionally substituted heterocyclylalkenylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkenylene group and Rb is an optionally substituted heterocyclyl group as defined above e.g., 3-(morpholin-4-yl)prop-1-enyl, 3-(piperidin-1-yl)prop-1-enyl, 3-(4-methylpiperazin-1-yl)prop-1-enyl, and the like.
xe2x80x9cOptionally substituted heterocyclylalkynylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkynyl group and Rb is an optionally substituted heterocyclyl group as defined above e.g., 3-(morpholin-4-yl)prop-1-ynyl, 3-(piperidin-1-yl)lprop-1-ynyl, and the like.
xe2x80x9cOptionally substituted heterocyclylalkoxyxe2x80x9d means a radical xe2x80x94OR where R is an optionally substituted heterocyclylalkyl group as defined above, e.g., 2-(morpholin-4-yl)-ethoxy, 3-(piperazin-1-yl)propoxy, 2-[2-oxopyrrolidin-1-yl]ethoxy, and the like.
xe2x80x9cOptionally substituted heterocyclylalkylaminoxe2x80x9d means a radical xe2x80x94NRaRb where Ra is hydrogen or alkyl and Rb is an optionally substituted heterocyclylalkyl group as defined above, e.g., 2-(pyrrolidin-2-yl)ethylamino, 3-(piperidin-1-yl)propylamino, and the like.
xe2x80x9cOptionally substituted heteroaralkyloxy means a radical xe2x80x94Oxe2x80x94Ra where Ra is a heteroaralkyl radical e.g. 2-(pyridin-3-yl)ethoxy, 2-[3(2H)-pyridazon-1-yl]ethoxy and the like.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, xe2x80x9caryl group optionally mono- or di- substituted with an alkyl groupxe2x80x9d means that the alkyl may but need not be present, and the description includes situations where the aryl group is mono- or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.
xe2x80x9cAmino protecting groupxe2x80x9d refers to those organic groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures e.g., benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trifluoroacetyl, and the like.
The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th edition J. March, John Wiley and Sons, New York, 1992).
A xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. xe2x80x9cA pharmaceutically acceptable excipientxe2x80x9d as used in the specification and claims includes both one and more than one such excipient.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include:
(1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4xe2x80x2-methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
xe2x80x9cPro-drugsxe2x80x9d means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl grojup, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula (I), and the like.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease includes:
(1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease,
(2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or
(3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
The naming and numbering of the compounds of this invention is illustrated below. 
The nomenclature used in this application is generally based on the IUPAC recommendations, e.g., a compound of formula (I):
where R1, R2, R4, R6 are hydrogen, 
xe2x80x83is 4-(3-hydroxypropyl)phenyl and 
xe2x80x83is 4-fluorophenyl is named 5-amino-1-(4-fluorophenyl)-4-[4-(3-hydroxypropyl)-benzoyl]parazole.
where R1, R2, R4, R6 are hydrogen, 
xe2x80x83is 3-[3-(morpholin-4-yl)prop-1-ynyl]-phenyl and 
xe2x80x83is 4-fluorophenyl is named 5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylprop-1-ynyl)benzoyl]pyrazole.
While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula (I) are preferred. For example,
(I) A preferred group of compounds is that wherein R3 is selected from:
(a) optionally substituted heterocyclyl;
(b) aryl or heteroaryl both optionally substituted with a substituent selected from halo, alkyl, amino, alkoxy, carboxy, lower alkoxy carbonyl, SO2Rxe2x80x2 (where Rxe2x80x2 is alkyl) or SO2NHRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl);
(c) heteroalkyl;
(d) heteroalkenyl;
(e) heteroalkylamino;
(f) heteroalkoxy;
(g) optionally substituted heterocyclylalkyl or heterocyclyloxy;
(h) optionally substituted heterocyclylalkenyl;
(i) optionally substituted heterocyclylalyyl;
(j) optionally substituted heterocyclylalkoxy;
(k) optionally substituted heterocyclylalkylano;
(l) optionally substituted heterocyclylalkylcarbonyl;
(k) xe2x80x94Yxe2x80x94(alkylene)xe2x80x94R9 where Y is a single bond, xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94 and R9 is optionally substituted heteroaryl, xe2x80x94CONR12R13, SO2NR14, xe2x80x94SO2NR15R16 xe2x80x94NHSO2R17 or xe2x80x94NHSO2NR18R19 where R12, R13, R14, R15, R16 R17, R18 and R19 are independently of each other hydrogen, alkyl or heteroalkyl;
(l) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino;
(m) arylaminoalkylene or heteroarylaminoalkylene; or
(n) Z-alkylene-NR30R31 where Z is xe2x80x94NHxe2x80x94, xe2x80x94N(alkyl)xe2x80x94 or xe2x80x94Oxe2x80x94, and R30 and R31 are independently of each other, hydrogen, alkyl or heteroalkyl.
Within the above preferred group, more preferred groups of compounds are those wherein, A and B are aryl, preferably phenyl.
Within the above preferred and more preferred groups, an even more preferred group of compounds is that wherein:
Rxe2x80x2 is hydrogen;
R2 is hydrogen or alkyl, preferably hydrogen or methyl, more preferably hydrogen.
R4 is hydrogen, halo or alkyl, preferably hydrogen, chloro, fluoro or methyl, more preferably hydrogen.
Within the above preferred and more preferred groups, a particularly preferred group of compounds is that wherein R3 is at the 3-position and is optionally substituted heteroaryl, preferably pyridinyl, N-oxidopyridinyl or pyridonyl.
Another particularly preferred group of compounds is that wherein R3 is at the 3-position and is optionally substituted phenyl, preferably sulfamoylphenyl, alkylsulfamoylphenyl, carboxyphenyl, carboxamidophenyl, alkoxycarbonylphenyl, alkylaminocarbonylphenyl or dialkylaminocarbonylphenyl.
A third particularly preferred group of compounds is that wherein:
R3 is at the 3-position and is selected from:
(a) heteroalkyl;
(b) heteroalkoxy;
(c) heteroalkylamino;
(d) optionally substituted heterocyclylalkyl;
(e) optionally substituted heterocyclylalkoxy;
(f) optionally substituted heterocyclylalkylamino;
(g) xe2x80x94Yxe2x80x94(alkylene)xe2x80x94R9 where Y is a single bond, xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94 and R9 is optionally substituted heteroaryl, xe2x80x94CONR12R13, SO2R14, xe2x80x94SO2NR15R16xe2x80x94NHSO2R17 or xe2x80x94NHSO2NR18R19 where R12, R13, R14, R15, R16 R17, R18 and R19 are independently of each other hydrogen, alkyl or heteroalkyl; or
(h) Z-alkylene-NR30R31 where Z is xe2x80x94NHxe2x80x94, xe2x80x94N(alkyl)xe2x80x94 or xe2x80x94Oxe2x80x94, and R30 and
R31 are independently of each other, hydrogen, alkyl or heteroalkyl.
Preferred groups for R3 include amino, 3-dimethylaminopropoxy, 2-dimethylaminoethoxy, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 2-dimethylaminoethylamino, 3-dimethylaminopropylamino, 3-dimethylaminoprop-1-enyl, 3-dimethylaminoprop-1-ynyl and 2-dimethylaminoethylcarbonyl, preferably amino.
Another group of preferred groups for R3 is selected from 3-(morpholin-4-yl)propoxy, 2-(morpholin-4-yl)ethoxy, 3-(morpholin4-yl)propyl, 2-(morpholin-4-yl)ethyl, 4-(morpholin-4-yl)butyl, 3-(morpholin-4-yl)propylamino, 2-(morpholin-4-yl)-ethylamino, 3-(morpholin-4-yl)-prop-1-enyl, 3-(morpholin-4-yl)prop-1-ynyl, 4-methylpiperazin-1-yl, piperazin-1-yl, pyridin-3-yl, morpholin-4-ylmethylcarbonyl, 3-dimethylaminoprop-1-enyl, 3-dimethylaminoprop-1-ynyl, 2-aminosulfonylethyl, 2-aminosulfonylethenyl, acetylamino and trifluoroacetylamino, preferably 2-(morpholin-4-yl)ethoxy and 3-(morpholin-4-yl)-propyl.
A fourth group of particularly preferred compounds is that where R5 is halo or alkyl and R6 is hydrogen, halo or alkyl, preferably R5 is 4-F or 2-Me and R6 is hydrogen, or R5 is 2-F and R6 is 4-F.
Exemplary particularly preferred compounds are:
5-amino-1-(4-fluorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazole.
5-amino-1-(2,4-difluorophenyl)-4-[3-(3-morpholin-4-ylpropyl)benzoyl]pyrazole.
5-amino-4-(3-aminobenzoyl)-1-(4-fluorophenyl)pyrazole.
5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropyl)benzoyl]pyrazole.
5-amino-4-[3-(2-aminosulfonylethenyl)benzoyl]-1-(4-fluorophenyl)pyrazole.
5-amino-4-(3-acetylaminobenzoyl)-1-phenylpyrazole.
5-amino-4-[3-(2-aminoethyl)benzoyl]-1-(4-fluorophenyl)pyrazole.
5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropylamino)benzoyl]pyrazole.
5-amino-4-[3-(2-aminosulfonylethyl)benzoyl]-1-(4-fluorophenyl)pyrazole.
5-amino-1-(4-fluorophenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole.
5-amino-1-(2-methylphenyl)-4-[3-(pyridin-3-yl)benzoyl]pyrazole.
5-amino-1-(2-methylphenyl)-4-[3-(N-oxidopyridin-3-yl)benzoyl]pyrazole.
5-amino-4-[3-(2,3-dihydroxypropoxy)benzoyl]-1-(4-fluorophenyl)pyrazole.
5-amino-4-[3-(1,2-dihydroxyethyl)benzoyl]-1-(4-fluorophenyl)pyrazole.
5-amino-1-(4-fluorophenyl)-4-[3-sulfamoylbenzoyl]pyrazole.
Compounds of this invention can be made by the methods depicted in the reaction schemes shown below.
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemie, or Sigma (St. Louis, Mo., USA) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser""s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd""s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March""s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock""s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.
The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Schemes A, B and C describe methods to generate the compounds of Formula (I). 
In general, compounds of Formula (I) can be prepared by following either method (a) or (b) as described below.
Method (a)
Reaction of a 2-ketoacetonitrile of formula 1 [where Z is halo (e.g., bromo or iodo), alkoxy, nitro or acetylamino] with N,N-diphenylformamidine gives a 2-keto-3-phenylamino-acrylonitrile of formula 2. The reaction occurs upon heating in a high boiling aromatic hydrocarbon such as toluene, xylene, and the like.
In general, compounds of formula 1 are either commercially available or they can be prepared by methods well known in the art. For example, 2-aroylacetonitriles of formula 1 such as 4-methoxybenzoylacetonitrile, 3-nitrobenzoylacetonitrile are commercially available. Others can be prepared by treating acetonitrile with a base such as n-butyllithium followed by reaction of the formed acetonitrile anion with an aroyl/heteroaroyl halide or an aryl/heteroaryl ester as described in Sjogren, E. B., et al., J. Med. Chem, 34, 3295, (1991).
Reaction of the 2-keto-3-phenylaminoacrylonitrile of formula 2 with a hydrazine of formula 3 provides a 5-amino-4-ketopyrazole of formula 4. This reaction is generally carried out in a polar solvent such as ethanol, isopropanol, and the like. Aryl/heteroaryl hydrazines of formula 2 such as 2- or 3-chlorophenylhydrazine, 2-,3-, or 4-fluorophenylhydrazine, phenylhydrazine, 2-hydrazinopyridine, 2-hydrazinobenzothiazole, 2-hydrazinoquinoline etc., are commercially available.
Compound 4 is then converted to a compound of Formula (I) where R1 is hydrogen and R3 is as defined in the Summary of the Invention by methods well known in the art. Some such procedures are described below.
(i) A compound of Formula (I) where R3 is heterocyclylalkyloxy can be prepared from a compound of formula 4 where Z is alkoxy as shown below: 
A compound of Formula (I) where R3 is heterocyclylalkloxy can be prepared from a compound of formula 4 where Z is alkoxy by first de-alkylating the alkoxy group to give the corresponding compound of formula 5 where Z is hydroxy followed by reaction with a heterocyclylalkyl halide [e.g., 4-(2-chloroethyl)morpholine, 1-(2-chloroethyl)pyrrolidine, and the like]. The de-alkylation reaction is carried out either with boron tribromide in a halogenated organic solvent such as dichloromethane or by heating 4 in neat pyridinium hydrochloride. The alkylation is carried out in the presence of a base (such as potassium carbonate, cesium carbonate, and the like) in a polar organic solvent such as acetonitrile, dimethylformamide, acetone, and the like.
Alternatively, a heterocyclylalkyl group can be attached by reacting 5 with an alkyl dihalide followed by the reaction of the resulting haloalkyloxy intermediate with a heterocyclyl group (e.g., piperazine, morpholine, pyrrolidine, and the like) under the reaction conditions described above. Alkyl dihalides such as 1-bromo-2-chloroethane, 1-chloro-3-iodopropane, and the like, are commercially available.
(ii) A compound of Formula (I) where R3 is xe2x80x94Oxe2x80x94(alkylene)xe2x80x94R9 (where R9 is xe2x80x94COOH, xe2x80x94COR10, xe2x80x94COOR11 or xe2x80x94CONR12R13) can be prepared from a compound of formula 5 as shown below: 
A compound of Formula (I) where R3 is xe2x80x94Oxe2x80x94(alkylene)xe2x80x94COOR11 is prepared by reacting a compound of formula 5 with an alkylating agent of formula Xxe2x80x94(alkylene)xe2x80x94CO2R11 where X is a halo group. Hydrolysis of the ester group provides the free acid (R9 is xe2x80x94COOH) which can be converted to a compound of Formula (I) where R9=xe2x80x94CONR12R13, if desired, by treating the acid with an amine of formula NR12R13 (where R12 and R13 are as defined in the Summary of the Invention) in the presence of a suitable coupling agent (e.g., carbonyl diimidazole, N,N-dicyclohexylcarbodiimide and the like).
A compound of Formula (I) where R9 is xe2x80x94COR10 can be prepared from a compound of Formula (I) where R9 is xe2x80x94COOH by first converting the acid to a Weinreb amide followed by treatment with either a Grignard reagent or organolithium reagent of formula R10MgBr or R10Li, respectively.
(iii) A compound of Formula (I) where R3 is xe2x80x94NHxe2x80x94(alkylene)xe2x80x94R9 where R9 is xe2x80x94COOH, xe2x80x94COR10, xe2x80x94COOR11, xe2x80x94CONR12R13 or heterocyclylalkylamino can be prepared from a compound of formula 4 where Z is a nitro group by reducing the nitro group to the amino group and then following the procedures described above.
(iv) A compound of Formula (I) where R3 is heteroalkenyl, heteroalkynyl, heterocyclylalkenyl, heterocyclylalkynyl, heteroalkyl or heterocyclylalkyl can be prepared as shown below. 
A compound of Formula (I) where R3 is heteroalkenyl, heteroalkynyl, heterocyclylalkenyl or heterocyclylalkynyl can be prepared by reacting a compound of formula 4 where Z is halo with a heteroalkene, heteroalkyne, heterocyclylalkene or heterocyclylalkyne respectively in the presence of a palladium (II) catalyst such as dichlorobis(triphenylphosphine)-palladium (II) in an organic base such as diisopropylamine, and the like. Heteroalkenes, heteroalkynes such as allyl alcohol, propargyl alcohol, 3-butyn-1-ol, propargylamine are commercially available. Heterocyclylalkyne can be prepared by reacting an alkynyl halide with a heterocycle. For example, 2-morpholin-1-ylprop-1-yne can be prepared by reacting propargyl bromide with morpholine. Reduction of the double or triple bond under catalytic hydrogenation reaction conditions provides the corresponding compound of Formula (I) where R3is a heterocyclylalkyl or heteroalkyl group.
(v) A compound of Formula (D) where R3 is xe2x80x94NHSO2R6, xe2x80x94NHSO2NR7R8 or NHC(X)R23R24 (where X is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94) can be prepared from a compound of Formula (I) where R3 is amino by following the synthetic procedures described in PCT Application No. WO 97/46524.
A compound of Formula (I) where R1 is an acyl group can be prepared by reacting the the corresponding compound of Formula (I) where R1 is hydrogen with an acylating reagent of formula R1COL where L is a leaving group under acylating reaction conditions such as halo. The reaction is carried out in the presence of a base such as sodium hydroxide, cesium carbonate, and the like.
Method (b)
Alternatively, a compound of Formula (I) can be prepared from an ester of formula 6 where Z is as defined above, by first converting the Z group in compound 6 to the desired R3 group utilizing the reaction conditions described in method (a)(i-v) above. Condensation of 7 with acetonitrile anion gives a 2-ketoacetonitrile of formula 8 which is then converted to a compound of Formula (I) utilizing the reaction conditions described in method (a) above.
Compounds of Formula (I) where R2 is thioalkyl or alkyl can be prepared by following the procedures described in U.S. Pat. No. 5,712,303. 
Condensation of 2-cyano-3-ethoxyacrylate of formula 9 with a hydrazine of formula 3 provides a 5-amino-4-ethoxycarbonyl pyrazole of formula 10. The condensation reaction is carried out in a suitable polar organic solvent such as ethanol, isopropanol, and the like. Hydrolysis of 10 with an aqueous base (e.g., sodium hydroxide, lithium hydroxide, and the like) in an alcoholic organic solvent (e.g., methanol, ethanol, and the like) provides the corresponding 5-amino-4-carboxypyrazole of formula 11. Treatment of 11 with dipyridyldisulfide followed by reaction of the resulting thiopyridyl ester derivative 12 with an organometallic reagent such as a Grignard reagent or an organolithium reagent shown above provides a compound of Formula (I). 
Thermal decarboxylation of a 5-amino-4-carboxypyrazole of formula 11 gives the corresponding 5-aminopyrazole of formula 13. Compound 13 is then converted to a compound of Formula (I) as shown in method (a) or (b) above.
In method (a), a compound of formula 13 is converted to a compound of Formula (I) by first protecting the amino group in compound 13 with a suitable amino protecting group (e.g., tert-butoxycarbonyl, and the like) to give the corresponding amino-protected compound of formula 14. Treatment of 14 with an acid derivative of formula R3COL where L is a leaving group under organometallic displacement reaction conditions [e.g., alkoxy (preferably methoxy or ethoxy), dialkylamino, or preferably N,O-dimethylhydroxylamino] followed by the removal of the amino protecting group then provides a compound of Formula (I). The nucleophilic substitution is carried out in the presence of 2 equivalents of an alkyllithium (e.g., tert-butyllithium, and the like) and in an aprotic organic solvent such as tetrahydrofuran. The reaction conditions employed for the removal of the amino protecting group depends on the nature of the protecting group. For example, if tert-butoxycarbonyl is the protecting group, it is removed by treatment with an acid such as trifluroacetic acid, hydrochloric acid, and the like.
Acid derivatives of formula R3COL can be prepared by methods well known in the field of organic chemistry. For example, an acid derivative where L is a N,O-dimethylhydroxylamino group can be prepared from its corresponding acid by first converting the acid to the acid chloride with a suitable chlorinating agent such as oxalyl chloride, followed by treatment with N,O-dimethylhydroxylamine hydrochloride in the presence of an organic base such as triethylamine.
In method (b), a compound of formula 10 is brominated to give the 5-amino-4-bromopyrazole of formula 15. The bromination reaction is carried out with a suitable brominating agent such as N-bromosuccinimide in a suitable polar organic solvent such as dimethylformamide. Compound 15 is then converted to a compound of Formula (I) utilizing the reaction conditions described in Scheme C, method (a) above.
The compounds of Formula (I) are p38 MAP kinase inhibitors and therefore compounds of Formula (I) and compositions containing them are useful in the treatment of diseases such as rheumatoid arthritis, osteoarthritis, spondylitis, bone resorption diseases, sepsis, septic shock, toxic shock syndrome, endotoxic shock, tuberculosis, atherosclerosis, diabetes, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, fever, periodontal diseases, ulcerative colitis, pyresis, Alzheimer""s and Parkinson""s diseases.
The ability of the compounds of Formula (I) to inhibit p38 MAP kinase was demonstrated by the in vitro assay described in Example 15. The ability of the compounds of Formula (I) to inhibit the release of TNF-xcex1 was demonstrated by the in vitro and the in vivo assays described in detail in Examples 16 and 17, respectively. The anti-inflammatory activity of the compounds of this invention was determined utilizing adjuvant induced arthritis in rats assay described in Example 18.
In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
Therapeutically effective amounts of compounds of Formula (I) may range from approximately 0.1-50 mg per kilogram body weight of the recipient per day; preferably about 1-30 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 70 mg to 2.1 g per day.
In general, compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
The compositions are comprised of in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I). Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
Other suitable pharmaceutical excipients and their formulations are described in Remington""s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations containing a compound of Formula (I) are described in Example 14.